1. Field of the Invention
This invention relates to treatment for inhibiting the growth or replication of viruses of the Human Immunodeficiency Virus (HIV) group, to compounds useful therein, and to pharmaceutical formulations incorporating such compounds.
2. Background of the Invention
Viruses are the smallest known infectious agents. They are made up of a nucleic acid (either Deoxyribonucleic Acid (DNA) or Ribonucleic Acid (RNA)) and viral proteins which are encased in a protein shell.
Viral infections, as a group, are among the most difficult infections to treat because of the way viruses replicate and interact with the cells which they infect. Thus current methods of treatment directed towards preventing the growth or replication of viruses often result in some degree of disturbance to the host cell's metabolism, with resultant toxicity to the host cells.
Generally, viruses first bind to the outer membrane of a particular host cell. After binding occurs, the viral nucleic acids (DNA or RNA) along with selected viral proteins enter into the host cell.
The viral nucleic acids then take over the metabolic machinery of the host cell and force the host cell to produce viral nucleic acid and proteins, which then assemble and are eventually released from the cell. Since release of the virus causes the cell membrane to rupture, a completed viral replication cycle results in the death of the host cell.
Viruses are generally divided into DNA or RNA viruses (depending on the type of nucleic acid they contain) and are further subdivided into various families.
Retroviruses are RNA viruses which contain high molecular weight RNA, traces of DNA, and various enzymes, including reverse transcriptase and nucleases enclosed by a protein coating. This type of virus first binds to the outer membrane of an appropriate cell, followed by injection of viral RNA and reverse transcriptase into the host cell.
Reverse transcriptase uses the viral RNA as a template to produce a complimentary DNA strand. This DNA becomes incorporated into the host's DNA and causes the host cell to produce viral RNA and viral proteins.
A subgroup of viruses in the Retrovirus family comprises human immunodeficiency viruses (HIV) which are known to preferentially attack cells of the human immune and nervous systems. HIV-I is the designation of the virus that is one of the etiologic agents for the development of Acquired Immune Deficiency Syndrome ("AIDS") in humans. It is known that HIV is transmitted by the exchange of bodily fluids, such as sexual secretions and blood, e.g., as a result of sexual contact, transfusions, or sharing of needles, for instance by intravenous drug users.
The HIV group infects and destroys the CD-4-T-lymphocytes (helper T-lymphocytes) and cells of the central nervous system.
Helper-T lymphocytes are vital to the immune system and are necessary for the immune system to be able to fight off opportunistic organisms such as pneumocystis carinii (which causes pneumonia), Toxoplasma gondii (Toxoplasmosis), viral infections caused by Herpes and Varicella viruses and also to prevent the formation of certain cancers, the most notable being Kaposi's Sarcoma.
Loss of these cells by HIV infection, either quantitatively or functionally, eventually leads to the loss of ability of the human immune system to fight off these diseases. Helper T-lymphocytes are also needed to fight HIV infection. It is the loss of helper T-cells which results in the severe immune deficiency that is one characteristic of AIDS. HIV infections of the central nervous system result in progressive loss of cerebral function, which culminates in AIDS dementia complex.
As of this date, AIDS caused by HIV has reached epidemic proportions in various parts of the world, including the United States.
Various known antiviral drugs have been tested for the prevention or treatment of HIV infections including alpha interferon, gamma interferon, azimexon, isopinosine, and Azidothymidine (or AZT). To date, the only substance which has achieved some clinical success is AZT. This substance is a synthetic thymidine analog that is incorporated into DNA and causes the premature termination of the synthesis of DNA. This results in the inhibition of viral replication, since DNA needed to produce the viral RNA is not produced.
However, DNA synthesis is also necessary for the continued normal functioning of the host cell. Consequently, administration of AZT results in the inhibition of host DNA synthesis with concomitant severe side effects, e.g., anemia, granulocytopenia, and thrombocytopenia.
Thus, there is a continuing need for better anti-HIV treatments and for better anti-HIV drugs.